7. Project Summary/Abstract Nonalcoholic fatty liver disease (NALFD) is a growing threat to public health: 24% of all adults, and over half of those with obesity or Type 2 diabetes (T2D), have NAFLD, which confers increased risk for liver failure, T2D, and cardiovascular disease. NAFLD is predicted to be the leading indication for liver transplantation by 2020. Although diet and exercise are proven to improve NAFLD, lifestyle changes are difficult to maintain for many patients. Currently there are no highly effective pharmacologic treatments for NAFLD, and significant need exists for therapeutic strategies to complement lifestyle changes. This proposal investigates a novel strategy to reduce liver fat and inflammation using growth hormone releasing hormone (GHRH), which augments endogenous GH secretion. On average, individuals with obesity have significant reductions in growth hormone secretion, which we hypothesize to contribute to the pathophysiology of NAFLD by promoting a pro- inflammatory milieu and altering hepatic lipid metabolism, increasing hepatic de novo lipogenesis. Our preliminary data demonstrate that GHRH decreases liver fat in HIV-infected individuals and, in obese individuals, reduces systemic inflammation and improves carotid intima-media thickness, a marker of subclinical atherosclerosis. These data support the need to study the effects of GHRH on liver fat and histology in obese individuals with NAFLD. The current research is proposed by collaborating Co-Principal Investigators, Dr. Corey, a hepatologist with significant investigative and clinical research experience in NAFLD, and Dr. Stanley, an endocrinologist with significant research experience in hormone dynamics, lipid metabolism, and use of GHRH. The proposal will investigate the efficacy of GHRH in a 12-month randomized controlled trial in 76 obese adults who have established NAFLD on liver biopsy or ?5% hepatic fat fraction on magnetic resonance spectroscopy (MRS). A 6-month open-label phase will follow the randomized phase in order to provide all participants with the opportunity to receive active treatment. The study hypotheses are as follows: Aim 1: Compared to placebo, GHRH will significantly decrease hepatic fat as measured by MRS (primary endpoint) and improve liver histology as assessed by reduction in NAFLD activity score and its individual components. Aim 2: GHRH will alter hepatic lipid metabolism by decreasing hepatic de novo lipogenesis and increasing expression of lipolytic genes, and will also reduce the hepatic expression of lipogenic, pro- inflammatory and fibrogenic genes. Aim 3: Finally, given that cardiovascular disease is the leading cause of death in NAFLD, and that preliminary data strongly suggest a benefit of GHRH to reduce subclinical atherosclerosis, we hypothesize that GHRH will decrease coronary artery calcium scores and overall plaque burden and will improve lipids and circulating markers of cardiovascular disease. If these hypotheses are correct, the proposed studies will represent significant progress toward the development of therapies for NAFLD in obesity.